Project acronym ACTIVATION OF XCI
Project Molecular mechanisms controlling X chromosome inactivation
Researcher (PI) Joost Henk Gribnau
Host Institution (HI) ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Call Details Starting Grant (StG), LS2, ERC-2010-StG_20091118
Summary In mammals, gene dosage of X-chromosomal genes is equalized between sexes by random inactivation of either one of the two X chromosomes in female cells. In the initial phase of X chromosome inactivation (XCI), a counting and initiation process determines the number of X chromosomes per nucleus, and elects the future inactive X chromosome (Xi). Xist is an X-encoded gene that plays a crucial role in the XCI process. At the start of XCI Xist expression is up-regulated and Xist RNA accumulates on the future Xi thereby initiating silencing in cis. Recent work performed in my laboratory indicates that the counting and initiation process is directed by a stochastic mechanism, in which each X chromosome has an independent probability to be inactivated. We also found that this probability is determined by the X:ploïdy ratio. These results indicated the presence of at least one X-linked activator of XCI. With a BAC screen we recently identified X-encoded RNF12 to be a dose-dependent activator of XCI. Expression of RNF12 correlates with Xist expression, and a heterozygous deletion of Rnf12 results in a marked loss of XCI in female cells. The presence of a small proportion of cells that still initiate XCI, in Rnf12+/- cells, also indicated that more XCI-activators are involved in XCI. Here, we propose to investigate the molecular mechanism by which RNF12 activates XCI in mouse and human, and to search for additional XCI-activators. We will also attempt to establish the role of different inhibitors of XCI, including CTCF and the pluripotency factors OCT4, SOX2 and NANOG. We anticipate that these studies will significantly advance our understanding of XCI mechanisms, which is highly relevant for a better insight in the manifestation of X-linked diseases that are affected by XCI.
Summary
In mammals, gene dosage of X-chromosomal genes is equalized between sexes by random inactivation of either one of the two X chromosomes in female cells. In the initial phase of X chromosome inactivation (XCI), a counting and initiation process determines the number of X chromosomes per nucleus, and elects the future inactive X chromosome (Xi). Xist is an X-encoded gene that plays a crucial role in the XCI process. At the start of XCI Xist expression is up-regulated and Xist RNA accumulates on the future Xi thereby initiating silencing in cis. Recent work performed in my laboratory indicates that the counting and initiation process is directed by a stochastic mechanism, in which each X chromosome has an independent probability to be inactivated. We also found that this probability is determined by the X:ploïdy ratio. These results indicated the presence of at least one X-linked activator of XCI. With a BAC screen we recently identified X-encoded RNF12 to be a dose-dependent activator of XCI. Expression of RNF12 correlates with Xist expression, and a heterozygous deletion of Rnf12 results in a marked loss of XCI in female cells. The presence of a small proportion of cells that still initiate XCI, in Rnf12+/- cells, also indicated that more XCI-activators are involved in XCI. Here, we propose to investigate the molecular mechanism by which RNF12 activates XCI in mouse and human, and to search for additional XCI-activators. We will also attempt to establish the role of different inhibitors of XCI, including CTCF and the pluripotency factors OCT4, SOX2 and NANOG. We anticipate that these studies will significantly advance our understanding of XCI mechanisms, which is highly relevant for a better insight in the manifestation of X-linked diseases that are affected by XCI.
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-04-01, End date: 2016-03-31
Project acronym BioNanoPattern
Project Protein nano-patterning using DNA nanotechnology; control of surface-based immune system activation
Researcher (PI) Thomas Harry SHARP
Host Institution (HI) ACADEMISCH ZIEKENHUIS LEIDEN
Call Details Starting Grant (StG), LS9, ERC-2017-STG
Summary Protein nanopatterning concerns the geometric arrangement of individual proteins with nanometre accuracy. It is becoming apparent that protein nanopatterns are essential for cellular function, and have roles in cell signalling and protection, phagocytosis and stem cell differentiation. Recent research indicates that our immune system is activated by nanopatterned antibody platforms, which initiate the classical Complement pathway by binding to the first component of Complement, the C1 complex. DNA nanotechnology can be used to form self-assembled nanoscale structures, which are ideal for use as templates to pattern proteins with specific geometries and nanometre accuracy. I propose to use DNA to nanopattern antigens and agonistic aptamers with defined geometry to study and control Complement pathway activation by the C1 complex.
To develop and demonstrate the potential use of DNA to nanopattern proteins, the first aim of this proposal is to design DNA nanotemplates suitable for patterning antibody-binding sites. Antibodies and C1 will bind with specific geometry, and the relationship between antibody geometry and Complement activation will be assessed using novel liposome assays. Using DNA to mimic antigenic surfaces will enable high-resolution structure determination of DNA-antibody-C1 complexes, both in solution and on lipid bilayer surfaces, using phase plate cryo-electron microscopy to elucidate the structure-activation relationship of C1.
The second aim of this proposal is to evolve agonistic aptamers that directly bind to and activate C1, and incorporate these into DNA nanotemplates. These nanopatterned aptamers will enable further study of C1 activation, and allow direct targeting of Complement activation to specific cells within a population of cell types to demonstrate targeted cell killing. This may open up new and highly efficient ways to activate our immune system in vivo, with potential for targeted anti-tumour immunotherapies.
Summary
Protein nanopatterning concerns the geometric arrangement of individual proteins with nanometre accuracy. It is becoming apparent that protein nanopatterns are essential for cellular function, and have roles in cell signalling and protection, phagocytosis and stem cell differentiation. Recent research indicates that our immune system is activated by nanopatterned antibody platforms, which initiate the classical Complement pathway by binding to the first component of Complement, the C1 complex. DNA nanotechnology can be used to form self-assembled nanoscale structures, which are ideal for use as templates to pattern proteins with specific geometries and nanometre accuracy. I propose to use DNA to nanopattern antigens and agonistic aptamers with defined geometry to study and control Complement pathway activation by the C1 complex.
To develop and demonstrate the potential use of DNA to nanopattern proteins, the first aim of this proposal is to design DNA nanotemplates suitable for patterning antibody-binding sites. Antibodies and C1 will bind with specific geometry, and the relationship between antibody geometry and Complement activation will be assessed using novel liposome assays. Using DNA to mimic antigenic surfaces will enable high-resolution structure determination of DNA-antibody-C1 complexes, both in solution and on lipid bilayer surfaces, using phase plate cryo-electron microscopy to elucidate the structure-activation relationship of C1.
The second aim of this proposal is to evolve agonistic aptamers that directly bind to and activate C1, and incorporate these into DNA nanotemplates. These nanopatterned aptamers will enable further study of C1 activation, and allow direct targeting of Complement activation to specific cells within a population of cell types to demonstrate targeted cell killing. This may open up new and highly efficient ways to activate our immune system in vivo, with potential for targeted anti-tumour immunotherapies.
Max ERC Funding
1 499 850 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym BURSTREG
Project Single-molecule visualization of transcription dynamics to understand regulatory mechanisms of transcriptional bursting and its effects on cellular fitness
Researcher (PI) Tineke LENSTRA
Host Institution (HI) STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS
Call Details Starting Grant (StG), LS1, ERC-2017-STG
Summary Transcription in single cells is a stochastic process that arises from the random collision of molecules, resulting in heterogeneity in gene expression in cell populations. This heterogeneity in gene expression influences cell fate decisions and disease progression. Interestingly, gene expression variability is not the same for every gene: noise can vary by several orders of magnitude across transcriptomes. The reason for this transcript-specific behavior is that genes are not transcribed in a continuous fashion, but can show transcriptional bursting, with periods of gene activity followed by periods of inactivity. The noisiness of a gene can be tuned by changing the duration and the rate of switching between periods of activity and inactivity. Even though transcriptional bursting is conserved from bacteria to yeast to human cells, the origin and regulators of bursting remain largely unknown. Here, I will use cutting-edge single-molecule RNA imaging techniques to directly observe and measure transcriptional bursting in living yeast cells. First, bursting properties will be quantified at different endogenous and mutated genes to evaluate the contribution of cis-regulatory promoter elements on bursting. Second, the role of trans-regulatory complexes will be characterized by dynamic depletion or gene-specific targeting of transcription regulatory proteins and observing changes in RNA synthesis in real-time. Third, I will develop a new technology to visualize the binding dynamics of single transcription factor molecules at the transcription site, so that the stability of upstream regulatory factors and the RNA output can directly be compared in the same cell. Finally, I will examine the phenotypic effect of different bursting patterns on organismal fitness. Overall, these approaches will reveal how bursting is regulated at the molecular level and how different bursting patterns affect the heterogeneity and fitness of the organism.
Summary
Transcription in single cells is a stochastic process that arises from the random collision of molecules, resulting in heterogeneity in gene expression in cell populations. This heterogeneity in gene expression influences cell fate decisions and disease progression. Interestingly, gene expression variability is not the same for every gene: noise can vary by several orders of magnitude across transcriptomes. The reason for this transcript-specific behavior is that genes are not transcribed in a continuous fashion, but can show transcriptional bursting, with periods of gene activity followed by periods of inactivity. The noisiness of a gene can be tuned by changing the duration and the rate of switching between periods of activity and inactivity. Even though transcriptional bursting is conserved from bacteria to yeast to human cells, the origin and regulators of bursting remain largely unknown. Here, I will use cutting-edge single-molecule RNA imaging techniques to directly observe and measure transcriptional bursting in living yeast cells. First, bursting properties will be quantified at different endogenous and mutated genes to evaluate the contribution of cis-regulatory promoter elements on bursting. Second, the role of trans-regulatory complexes will be characterized by dynamic depletion or gene-specific targeting of transcription regulatory proteins and observing changes in RNA synthesis in real-time. Third, I will develop a new technology to visualize the binding dynamics of single transcription factor molecules at the transcription site, so that the stability of upstream regulatory factors and the RNA output can directly be compared in the same cell. Finally, I will examine the phenotypic effect of different bursting patterns on organismal fitness. Overall, these approaches will reveal how bursting is regulated at the molecular level and how different bursting patterns affect the heterogeneity and fitness of the organism.
Max ERC Funding
1 950 775 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym COSMOS
Project Computational Simulations of MOFs for Gas Separations
Researcher (PI) Seda Keskin Avci
Host Institution (HI) KOC UNIVERSITY
Call Details Starting Grant (StG), PE8, ERC-2017-STG
Summary Metal organic frameworks (MOFs) are recently considered as new fascinating nanoporous materials. MOFs have very large surface areas, high porosities, various pore sizes/shapes, chemical functionalities and good thermal/chemical stabilities. These properties make MOFs highly promising for gas separation applications. Thousands of MOFs have been synthesized in the last decade. The large number of available MOFs creates excellent opportunities to develop energy-efficient gas separation technologies. On the other hand, it is very challenging to identify the best materials for each gas separation of interest. Considering the continuous rapid increase in the number of synthesized materials, it is practically not possible to test each MOF using purely experimental manners. Highly accurate computational methods are required to identify the most promising MOFs to direct experimental efforts, time and resources to those materials. In this project, I will build a complete MOF library and use molecular simulations to assess adsorption and diffusion properties of gas mixtures in MOFs. Results of simulations will be used to predict adsorbent and membrane properties of MOFs for scientifically and technologically important gas separation processes such as CO2/CH4 (natural gas purification), CO2/N2 (flue gas separation), CO2/H2, CH4/H2 and N2/H2 (hydrogen recovery). I will obtain the fundamental, atomic-level insights into the common features of the top-performing MOFs and establish structure-performance relations. These relations will be used as guidelines to computationally design new MOFs with outstanding separation performances for CO2 capture and H2 recovery. These new MOFs will be finally synthesized in the lab scale and tested as adsorbents and membranes under practical operating conditions for each gas separation of interest. Combining a multi-stage computational approach with experiments, this project will lead to novel, efficient gas separation technologies based on MOFs.
Summary
Metal organic frameworks (MOFs) are recently considered as new fascinating nanoporous materials. MOFs have very large surface areas, high porosities, various pore sizes/shapes, chemical functionalities and good thermal/chemical stabilities. These properties make MOFs highly promising for gas separation applications. Thousands of MOFs have been synthesized in the last decade. The large number of available MOFs creates excellent opportunities to develop energy-efficient gas separation technologies. On the other hand, it is very challenging to identify the best materials for each gas separation of interest. Considering the continuous rapid increase in the number of synthesized materials, it is practically not possible to test each MOF using purely experimental manners. Highly accurate computational methods are required to identify the most promising MOFs to direct experimental efforts, time and resources to those materials. In this project, I will build a complete MOF library and use molecular simulations to assess adsorption and diffusion properties of gas mixtures in MOFs. Results of simulations will be used to predict adsorbent and membrane properties of MOFs for scientifically and technologically important gas separation processes such as CO2/CH4 (natural gas purification), CO2/N2 (flue gas separation), CO2/H2, CH4/H2 and N2/H2 (hydrogen recovery). I will obtain the fundamental, atomic-level insights into the common features of the top-performing MOFs and establish structure-performance relations. These relations will be used as guidelines to computationally design new MOFs with outstanding separation performances for CO2 capture and H2 recovery. These new MOFs will be finally synthesized in the lab scale and tested as adsorbents and membranes under practical operating conditions for each gas separation of interest. Combining a multi-stage computational approach with experiments, this project will lead to novel, efficient gas separation technologies based on MOFs.
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
Project acronym CRITIQUEUE
Project Critical queues and reflected stochastic processes
Researcher (PI) Johannes S.H. Van Leeuwaarden
Host Institution (HI) TECHNISCHE UNIVERSITEIT EINDHOVEN
Call Details Starting Grant (StG), PE1, ERC-2010-StG_20091028
Summary Our primary motivation stems from queueing theory, the branch of applied probability that deals with congestion phenomena. Congestion levels are typically nonnegative, which is why reflected stochastic processes arise naturally in queueing theory. Other applications of reflected stochastic processes are in the fields of branching processes and random graphs.
We are particularly interested in critically-loaded queueing systems (close to 100% utilization), also referred to as queues in heavy traffic. Heavy-traffic analysis typically reduces complicated queueing processes to much simpler (reflected) limit processes or scaling limits. This makes the analysis of complex systems tractable, and from a mathematical point of view, these results are appealing since they can be made rigorous. Within the large
body of literature on heavy-traffic theory and critical stochastic processes, we launch two new research lines:
(i) Time-dependent analysis through scaling limits.
(ii) Dimensioning stochastic systems via refined scaling limits and optimization.
Both research lines involve mathematical techniques that combine stochastic theory with asymptotic theory, complex analysis, functional analysis, and modern probabilistic methods. It will provide a platform enabling collaborations between researchers in pure and applied probability and researchers in performance analysis of queueing systems. This will particularly be the case at TU/e, the host institution, and at
the affiliated institution EURANDOM.
Summary
Our primary motivation stems from queueing theory, the branch of applied probability that deals with congestion phenomena. Congestion levels are typically nonnegative, which is why reflected stochastic processes arise naturally in queueing theory. Other applications of reflected stochastic processes are in the fields of branching processes and random graphs.
We are particularly interested in critically-loaded queueing systems (close to 100% utilization), also referred to as queues in heavy traffic. Heavy-traffic analysis typically reduces complicated queueing processes to much simpler (reflected) limit processes or scaling limits. This makes the analysis of complex systems tractable, and from a mathematical point of view, these results are appealing since they can be made rigorous. Within the large
body of literature on heavy-traffic theory and critical stochastic processes, we launch two new research lines:
(i) Time-dependent analysis through scaling limits.
(ii) Dimensioning stochastic systems via refined scaling limits and optimization.
Both research lines involve mathematical techniques that combine stochastic theory with asymptotic theory, complex analysis, functional analysis, and modern probabilistic methods. It will provide a platform enabling collaborations between researchers in pure and applied probability and researchers in performance analysis of queueing systems. This will particularly be the case at TU/e, the host institution, and at
the affiliated institution EURANDOM.
Max ERC Funding
970 800 €
Duration
Start date: 2010-08-01, End date: 2016-07-31
Project acronym CUTTINGBUBBLES
Project Bubbles on the Cutting Edge
Researcher (PI) Niels Gerbrand Deen
Host Institution (HI) TECHNISCHE UNIVERSITEIT EINDHOVEN
Call Details Starting Grant (StG), PE8, ERC-2010-StG_20091028
Summary Many processes in the chemical, petrochemical and/or biological industries involve three phase gas-liquidsolid flows, where the solid material acts as a catalyst carrier, the gas phase supplies the reactants for the (bio-)chemical transformations and the liquid phase carries the product. In these processes the performance and operation of the reactor is mostly constrained by the interfacial mass transfer rate and the achievable insitu heat removal rate. A micro-structured bubble column reactor that significantly improves these crucial properties is proposed in this project. This novel type of reactor takes advantage of micro-structuring of the catalyst carrier in the form of a wire-mesh (see Figure 1).
The aim of the wire-mesh is i) to cut bubbles into smaller pieces leading to a larger interfacial area, ii) to enhance the bubble interface dynamics and mass transfer due to the interaction between the bubbles and the wires, and iii) to save costs in practical operation due to the smaller required reactor volume and the fact that
there is no need for an external filtration unit.
Cutting edge three-phase direct numerical simulation (DNS) tools and novel non-invasive optical (highspeed camera) techniques are used to study the micro-scale interaction between bubbles and a wire-mesh to gain understanding of the splitting and merging of bubbles and associated mass transfer characteristics. Furthermore, a proof-of-principle of the micro-structured reactor will be given through lab-scale experiments and macroscopic Euler-Lagrange numerical simulations, employing bubble-wire interaction closures based on the DNS simulations.
In addition to the novel reactor type, the project will generate a broad set of fundamental numerical and experimental research tools that can be used for the improvement of various gas-liquid-solid processes.
Several large companies (AkzoNobel, DSM, Sabic and Shell) have indicated their interest in the proposed
project and would like to be involved in a users committee.
Summary
Many processes in the chemical, petrochemical and/or biological industries involve three phase gas-liquidsolid flows, where the solid material acts as a catalyst carrier, the gas phase supplies the reactants for the (bio-)chemical transformations and the liquid phase carries the product. In these processes the performance and operation of the reactor is mostly constrained by the interfacial mass transfer rate and the achievable insitu heat removal rate. A micro-structured bubble column reactor that significantly improves these crucial properties is proposed in this project. This novel type of reactor takes advantage of micro-structuring of the catalyst carrier in the form of a wire-mesh (see Figure 1).
The aim of the wire-mesh is i) to cut bubbles into smaller pieces leading to a larger interfacial area, ii) to enhance the bubble interface dynamics and mass transfer due to the interaction between the bubbles and the wires, and iii) to save costs in practical operation due to the smaller required reactor volume and the fact that
there is no need for an external filtration unit.
Cutting edge three-phase direct numerical simulation (DNS) tools and novel non-invasive optical (highspeed camera) techniques are used to study the micro-scale interaction between bubbles and a wire-mesh to gain understanding of the splitting and merging of bubbles and associated mass transfer characteristics. Furthermore, a proof-of-principle of the micro-structured reactor will be given through lab-scale experiments and macroscopic Euler-Lagrange numerical simulations, employing bubble-wire interaction closures based on the DNS simulations.
In addition to the novel reactor type, the project will generate a broad set of fundamental numerical and experimental research tools that can be used for the improvement of various gas-liquid-solid processes.
Several large companies (AkzoNobel, DSM, Sabic and Shell) have indicated their interest in the proposed
project and would like to be involved in a users committee.
Max ERC Funding
1 500 000 €
Duration
Start date: 2010-09-01, End date: 2015-08-31
Project acronym deFIBER
Project Dissecting the cellular and molecular dynamics of bone marrow fibrosis for improved diagnostics and treatment
Researcher (PI) Rebekka SCHNEIDER-KRAMANN
Host Institution (HI) ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Call Details Starting Grant (StG), LS4, ERC-2017-STG
Summary Bone marrow (BM) fibrosis is the continuous replacement of blood forming cells in the bone marrow by scar tissue, ultimately leading to failure of the body to produce blood cells. Primary myelofibrosis (PMF), an incurable blood cancer, is the prototypic example of the step-wise development of BM fibrosis. The specific mechanisms that cause BM fibrosis are not understood, in particular as the cells driving fibrosis have remained obscure.
My recent findings demonstrate that Gli1+ cells are fibrosis-driving cells in PMF, that their frequency correlates with fibrosis severity in patients, and that their ablation ameliorates BM fibrosis. These results indicate that Gli1+ cells are the primary effector cells in BM fibrosis and that they represent a highly attractive therapeutic target. This puts me in a unique position to vastly expand our knowledge of the BM fibrosis pathogenesis, improve diagnostics, and discover new therapeutic strategies for this fatal disease. I will do this by: 1) dissecting the molecular and cellular mechanisms of the fibrotic transformation, 2) defining the stepwise disease evolution by genetic fate tracing and analysis of the previously unknown critical effector cells of BM fibrosis , 3) understanding early forms of BM fibrosis for improved diagnostics in patients, all with the ultimate aim to identify novel therapeutic targets to directly block the cellular and molecular changes occuring in BM fibrosis.
I will apply state-of-the-art techniques, including genetic fate tracing experiments, conditional genetic knockout mouse models, tissue engineering of the bone marrow niche and in vivo and in vitro CRISPR/Cas9 gene editing, to unravel the complex molecular and cellular interaction between fibrosis-causing cells and the malignant hematopoietic cells. I will translate these findings into patient samples with the aim to improve the early diagnosis of the disease and to ultimately develop novel targeted therapies with curative intentions.
Summary
Bone marrow (BM) fibrosis is the continuous replacement of blood forming cells in the bone marrow by scar tissue, ultimately leading to failure of the body to produce blood cells. Primary myelofibrosis (PMF), an incurable blood cancer, is the prototypic example of the step-wise development of BM fibrosis. The specific mechanisms that cause BM fibrosis are not understood, in particular as the cells driving fibrosis have remained obscure.
My recent findings demonstrate that Gli1+ cells are fibrosis-driving cells in PMF, that their frequency correlates with fibrosis severity in patients, and that their ablation ameliorates BM fibrosis. These results indicate that Gli1+ cells are the primary effector cells in BM fibrosis and that they represent a highly attractive therapeutic target. This puts me in a unique position to vastly expand our knowledge of the BM fibrosis pathogenesis, improve diagnostics, and discover new therapeutic strategies for this fatal disease. I will do this by: 1) dissecting the molecular and cellular mechanisms of the fibrotic transformation, 2) defining the stepwise disease evolution by genetic fate tracing and analysis of the previously unknown critical effector cells of BM fibrosis , 3) understanding early forms of BM fibrosis for improved diagnostics in patients, all with the ultimate aim to identify novel therapeutic targets to directly block the cellular and molecular changes occuring in BM fibrosis.
I will apply state-of-the-art techniques, including genetic fate tracing experiments, conditional genetic knockout mouse models, tissue engineering of the bone marrow niche and in vivo and in vitro CRISPR/Cas9 gene editing, to unravel the complex molecular and cellular interaction between fibrosis-causing cells and the malignant hematopoietic cells. I will translate these findings into patient samples with the aim to improve the early diagnosis of the disease and to ultimately develop novel targeted therapies with curative intentions.
Max ERC Funding
1 498 544 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym DINOPRO
Project From Protist to Proxy:
Dinoflagellates as signal carriers for climate and carbon cycling during past and present extreme climate transitions
Researcher (PI) Appy Sluijs
Host Institution (HI) UNIVERSITEIT UTRECHT
Call Details Starting Grant (StG), PE10, ERC-2010-StG_20091028
Summary I propose to develop and apply a novel method for the integrated reconstruction of past changes in carbon cycling and climate change. This method will be based on combining a well-established sensitive paleoclimate proxy with a recent discovery: the stable carbon isotopic composition (δ13C) of marine dinoflagellates (algae) and their organic fossils (dinocysts) reflects seawater carbonate chemistry, particularly pCO2. Biological (culture) experiments will lead to new insights in dinoflagellate carbon acquisition, and enable quantification of the effect of carbon speciation on dinoflagellate δ13C. The rises in CO2 concentrations during the last century, and at the termination of the last glacial period will be used to test and calibrate the new method. The δ13C of fossil dinoflagellate cysts will subsequently be used to reconstruct surface ocean pCO2 and ocean acidification during a past analogue of rapidly rising carbon dioxide concentrations, 55 million years ago. My research will shed new light on processes such as ocean acidification and the marine carbon cycle as a whole. Past analogues of rapid carbon injection can aid in the quantification of climate change and identification of vulnerable biological groups, critical to identify ‘tipping points’ in system Earth. The study of dinoflagellate carbon isotopes comprises the initiation of a new research field and will provide constraints on ocean acidification in the past and its consequences in the future.
Summary
I propose to develop and apply a novel method for the integrated reconstruction of past changes in carbon cycling and climate change. This method will be based on combining a well-established sensitive paleoclimate proxy with a recent discovery: the stable carbon isotopic composition (δ13C) of marine dinoflagellates (algae) and their organic fossils (dinocysts) reflects seawater carbonate chemistry, particularly pCO2. Biological (culture) experiments will lead to new insights in dinoflagellate carbon acquisition, and enable quantification of the effect of carbon speciation on dinoflagellate δ13C. The rises in CO2 concentrations during the last century, and at the termination of the last glacial period will be used to test and calibrate the new method. The δ13C of fossil dinoflagellate cysts will subsequently be used to reconstruct surface ocean pCO2 and ocean acidification during a past analogue of rapidly rising carbon dioxide concentrations, 55 million years ago. My research will shed new light on processes such as ocean acidification and the marine carbon cycle as a whole. Past analogues of rapid carbon injection can aid in the quantification of climate change and identification of vulnerable biological groups, critical to identify ‘tipping points’ in system Earth. The study of dinoflagellate carbon isotopes comprises the initiation of a new research field and will provide constraints on ocean acidification in the past and its consequences in the future.
Max ERC Funding
1 498 800 €
Duration
Start date: 2010-09-01, End date: 2016-08-31
Project acronym ENABLE
Project Advancing cell based therapies by supporting implant survival
Researcher (PI) Jeroen Leijten
Host Institution (HI) UNIVERSITEIT TWENTE
Call Details Starting Grant (StG), LS7, ERC-2017-STG
Summary Tissue engineering aims at the creation of living implants to replace, repair, or regenerate damaged, diseased, or aged tissues, which holds tremendous possibilities to both extend our lives and improve our quality of life. During the last decades, our ability to create small tissues to heal small animals e.g. mice and rats has taken a breath taking leap. However, we have relentlessly struggled to create viable tissues of human-relevant sizes. Creating solid large tissues imposes lethal nutrient diffusion limitations, which causes the living implant to suffer from starvation, loss of function, and inevitable failure.
I hypothesize that this key challenge can be tackled by recruiting and developing advanced enabling nano- and micro-technologies. The ENABLE project begins with the design and development of a widely applicable platform that will enable large solid engineered tissues to survive and function by actively sustaining the implants metabolic needs. This platform is based on a unique two pronged strategy that rely on distinct technologies: oxygen releasing micromaterials, fabricated using a next-generation droplet generator, to enable short term survival of the implant, while embedded bioprinting will endow implants with a complex 3D vascular network to enable their long term survival. As proof of principle, the effects of ENABLE’s platform will be investigated using a critical bone defect in which I analyse the survival and function of the created living implants.
The anticipated outcomes of this proposal are three fold: first, I will develop a next-generation engineered tissue that will overcome the current size restrictions via the use of enabling technologies; second, I will reveal new knowledge on the role of the oxygen tension on vascularization and tissue formation by enabling control over the in vivo oxygen tension; and third, I will develop a novel strategy that enables the treatment of critical bone defects.
Summary
Tissue engineering aims at the creation of living implants to replace, repair, or regenerate damaged, diseased, or aged tissues, which holds tremendous possibilities to both extend our lives and improve our quality of life. During the last decades, our ability to create small tissues to heal small animals e.g. mice and rats has taken a breath taking leap. However, we have relentlessly struggled to create viable tissues of human-relevant sizes. Creating solid large tissues imposes lethal nutrient diffusion limitations, which causes the living implant to suffer from starvation, loss of function, and inevitable failure.
I hypothesize that this key challenge can be tackled by recruiting and developing advanced enabling nano- and micro-technologies. The ENABLE project begins with the design and development of a widely applicable platform that will enable large solid engineered tissues to survive and function by actively sustaining the implants metabolic needs. This platform is based on a unique two pronged strategy that rely on distinct technologies: oxygen releasing micromaterials, fabricated using a next-generation droplet generator, to enable short term survival of the implant, while embedded bioprinting will endow implants with a complex 3D vascular network to enable their long term survival. As proof of principle, the effects of ENABLE’s platform will be investigated using a critical bone defect in which I analyse the survival and function of the created living implants.
The anticipated outcomes of this proposal are three fold: first, I will develop a next-generation engineered tissue that will overcome the current size restrictions via the use of enabling technologies; second, I will reveal new knowledge on the role of the oxygen tension on vascularization and tissue formation by enabling control over the in vivo oxygen tension; and third, I will develop a novel strategy that enables the treatment of critical bone defects.
Max ERC Funding
1 500 000 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym ENCODING IN AXONS
Project Identifying mechanisms of information encoding in myelinated single axons
Researcher (PI) Maarten Kole
Host Institution (HI) KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary A major challenge in neuroscience is to understand how information is stored and coded within single nerve cells (neurons) and across neuron populations in the brain. Nerve cell fibres (axons) are thought to provide the wiring to connect neurons and conduct the electrical nerve impulse (action potential; AP). Recent discoveries, however, show that the initial part of axons actively participates in modulating APs and providing a means to enhance the computational repertoire of neurons in the central nervous system. To decrease the temporal delay in information transmission over long distances most axons are myelinated. Here, we will test the hypothesis that the degree of myelination of single axons directly and indirectly influences the mechanisms of AP generation and neural coding. We will use a novel approach of patch-clamp recording combined with immunohistochemical and ultrastructural identification to develop a detailed model of single myelinated neocortical axons. We also will investigate the neuron-glia interactions responsible for the myelination process and measure whether their development follows an activity-dependent process. Finally, we will elucidate the physiological and molecular similarities and discrepancies between myelinated and experimentally demyelinated single neocortical axons. These studies will provide a novel methodological framework to study central nervous system axons and yield basic insights into myelin physiology and pathophysiology.
Summary
A major challenge in neuroscience is to understand how information is stored and coded within single nerve cells (neurons) and across neuron populations in the brain. Nerve cell fibres (axons) are thought to provide the wiring to connect neurons and conduct the electrical nerve impulse (action potential; AP). Recent discoveries, however, show that the initial part of axons actively participates in modulating APs and providing a means to enhance the computational repertoire of neurons in the central nervous system. To decrease the temporal delay in information transmission over long distances most axons are myelinated. Here, we will test the hypothesis that the degree of myelination of single axons directly and indirectly influences the mechanisms of AP generation and neural coding. We will use a novel approach of patch-clamp recording combined with immunohistochemical and ultrastructural identification to develop a detailed model of single myelinated neocortical axons. We also will investigate the neuron-glia interactions responsible for the myelination process and measure whether their development follows an activity-dependent process. Finally, we will elucidate the physiological and molecular similarities and discrepancies between myelinated and experimentally demyelinated single neocortical axons. These studies will provide a novel methodological framework to study central nervous system axons and yield basic insights into myelin physiology and pathophysiology.
Max ERC Funding
1 994 640 €
Duration
Start date: 2011-04-01, End date: 2016-03-31
